1,4-dihydropyridines useful as pharmaceuticals

ABSTRACT

The invention provides compounds of the formula: ##STR1## The variables are defined in the specification. The compounds are useful e.g. for the curative or prophylactic treatment of allergic conditions.

This application derives priority from PCT/EP 90/00336 filed Mar. 20,1989 which now is International Publication Number WO 90/11280.

This invention relates to certain 4-heteroaryl-1,4-dihydropyridines.More particularly, this invention relates to certain3-alkoxycarbonyl-4-heteroaryl-2-(4-heteroaryl)phenyl-6-methyl-1,4-dihydropyridine-5-carboxamidederivatives which are potent and selective antagonists of plateletactivating factor (PAF) having clinical utility in the treatment ofallergic, hypersecretory and inflammatory conditions in humans andanimals.

Platelet activating factor (PAF:1-0-alkyl-2-acetyl-snglyceryl-3-phosphorylcholine) is an etherphospholipid whose structure was first elucidated in 1979. It isproduced by, released from and interacts with many pro-inflammatorycells, platelets and the kidney. In addition to potent plateletaggregating activity, PAF exhibits a wide spectrum of biologicalactivities elicited either directly or via the release of other powerfulmediators such as thromboxane A₂ or the leukotrienes. In vitro, PAFstimulates the movement and aggregation of neutrophils and the releasetherefrom of tissue-damaging enzymes and oxygen radicals. Theseactivities contribute to actions of PAF in vivo consistent with itplaying a significant role in inflammatory and allergic responses. Thus,intradermal PAF has been shown to induce an inflammatory response, withassociated pain, accumulation of inflammatory cells and increasedvascular permeability, comparable with the allergic skin reactionfollowing exposure to allergen. Similarly, both the acutebronchoconstriction and chronic inflammatory reactions elicited byallergens in asthma can be mimicked by intratracheal administration ofPAF. Accordingly agents which antagonise the actions of PAF and,consequently also prevent mediator release by PAF, will have clinicalutility in the treatment of a variety of allergic, inflammatory andhypersecretory conditions such as asthma, arthritis, rhinitis,bronchitis and urticaria.

In addition to the above, PAF has been implicated as being involved in anumber of other medical conditions. Thus in circulatory shock, which ischaracterised by systemic hypotension, pulmonary hypertension andincreased lung vascular permeability, the symptoms can be mimicked byinfusion of PAF. This, coupled with evidence showing that circulatingPAF levels are increased by endotoxin infusion, indicates that PAF is aprime mediator in certain forms of shock. Intravenous infusion of PAF atdoses of 20-200 pmol kg⁻¹ min⁻¹ into rats results in the formation ofextensive haemorrhagic erosions in the gastric mucosa and thus PAF isthe most potent gastric ulcerogen yet described whose endogenous releasemay underlie or contribute to certain forms of gastric ulceration.Psoriasis is an inflammatory and proliferative disease characterised byskin lesions. PAF is pro-inflammatory and has been isolated fromlesioned scale of psoriatic patients indicating PAF has a role in thedisease of psoriasis. Also increasing evidence supports a potentialpathophysiological role for PAF in cardiovascular disease. Thus recentstudies in angina patients show PAF is released during atrial pacing.Intracoronary injection of PAF in pigs induces a prolonged decrease incoronary flow and, in guinea pig hearts, it induces regional shuntingand ischaemia. In addition PAF has been shown to initiate thrombusformation in a mesenteric artery preparation, both when administeredexogenously and when released endogenously. More recently PAF has beenshown to play a role in brain ischaemia induced in animal models ofstroke.

Thus the compounds of the invention, by virtue of their ability toantagonise the actions of PAF, are of value in the treatment of theabove conditions.

Our co-pending published patent applications EP-A-258033, EP-A-266989,EP-A-294074 and EP-A-310386 disclose4-aryl-5-carbamoyl-1,4-dihydropyridines as PAF antagonists.

Thus the present invention provides compounds of the formula: ##STR2##and the pharmaceutically acceptable salts thereof, wherein R is athienyl, benzothienyl, furyl, benzofuranyl, pyridinyl, quinolinyl orisoquinolinyl group, said groups being optionally substituted by up to 3substituents each independently selected from nitro, halo, C₁ -C₄ alkyl,C₁ -C₄ alkoxy, aryl(C₁ -C₄)alkoxy, fluoro(C₁ -C₄)-alkoxy, C₁ -C₄alkylthio, C₁ -C₄ alkanesulphonyl, hydroxy, trifluoromethyl and cyano;either

R¹ and R² are each independently H or C₁ -C₆ alkyl; or R¹ and R², takentogether with the nitrogen atom to which they are attached, form apyrrolidinyl, piperidinyl, morpholinyl, piperazinyl, N'-(C₁ -C₄alkyl)piperazinyl or N'-(C₂ -C₄ alkanoyl)piperazinyl group;

R¹ is H or C₁ -C₄ alkyl and R² is cyano, C₃ -C₇ cycloalkyl, aryl,heteroaryl or a C₁ -C₄ alkyl group substituted by up to 2 substituentseach independently selected from C₃ -C₇ cycloalkyl, C₁ -C₄alkoxycarbonyl, aryl and heteroaryl;

R³ is C₁ -C₆ alkyl or aryl(C₁ -C₄)alkyl;

R⁴ is either (a) an imidazolyl, triazolyl, pyridinyl, pyridazinyl,pyrimidinyl, pyrazinyl, oxazolyl or thiazolyl group, said group beingoptionally benzo-, pyrido-, pyridazino-, pyrimido- or pyrazino-fused, or(b) an oxazolo- or thiazolo-fused imidazolyl group, R⁴ being optionallysubstituted by up to 3 substituents each independently selected from C₁-C₄ alkyl, C₁ -C₄ alkoxy, trifluoromethyl, cyano and halo.

"Aryl", used in the definition of R, R² and R³, is phenyl optionallysubstituted by up to 3 substituents each independently selected fromhalo, trifluoromethyl, C₁ -C₄ alkyl, hydroxy, C₁ -C₄ alkoxy, fluoro(C₁-C₄)alkoxy, (C₁ -C₄ alkoxy)carbonyl, C₁ -C₄ alkanesulphonyl, sulphamoyland cyano.

"Heteroaryl", used in the definition of R², is a 5- or 6-memberedaromatic heterocyclic group containing up to 3 heteroatoms each selectedfrom N, 0 and S and which may be optionally benzo-fused, said"heteroaryl" group being optionally substituted by up to 3 substituentseach independently selected from C₁ -C₄ alkyl, C₁ -C₄ alkoxy and halo.

Examples of suitable "heteroaryl" groups include pyridinyl, thiazolyl,thiadiazolyl, oxazolyl, oxadiazolyl, isoxazolyl and imidazolyl, any ofwhich may be optionally benzo-fused, said "heteroaryl" groups beingoptionally substituted by up to 3 substituents each independentlyselected from C₁ -C₄ alkyl, C₁ -C₄ alkoxy and halo.

Thus particular examples of R² as "heteroaryl" include pyridin-2-yl, 4-and 6-methylpyridin-2-yl, thiazol-2-yl, 4- and 5-methylthiazol-2-yl,5-methyl-1,3,4-thiadiazol-2-yl, 5-methyl-1,2,4-oxadiazol-3-yl,5-methylisoxazol-3-yl, benzothiazol-2-yl, 5-ethoxybenzothiazol-2-yl and1-methylimidazol-2-yl.

"Halo" is fluoro, chloro, bromo or iodo.

Alkyl, alkanesulphonyl and alkoxy groups containing 3 or more carbonatoms, and C₄ alkanoyl groups, may be straight or branched chain.

The pharmaceutically acceptable acid addition salts of the compounds offormula (I) are those formed from acids which form non-toxic acidaddition salts, for example the hydrochloride, hydrobromide, sulphate orbisulphate, phosphate, mono- or dihydrogen phosphate, acetate, citrate,fumarate, gluconate, lactate, maleate, succinate, tartrate,methanesulphonate, benzenesulphonate and p-toluenesulphonate.

Preferably, R is benzo[b]thien-3-yl, pyridin-2-yl, pyridin-3-yl, and2-chloropyridin-3-yl.

Preferably R¹ is H and R² is H, C₁ -C₄ alkyl, pyridinyl, thiazolyl or1-(phenyl)ethyl.

Most preferably R¹ is H and R² is pyridin-2-yl.

Preferably, R³ is methyl, ethyl or benzyl ring-substituted by up to 2halo substituents.

Most preferably, R³ is ethyl.

Preferably, R⁴ is 2-methylimidazo[4,5-c]pyridin-1-yl, imidazol-1-yl,benzimidazol-1-yl, 2-methylbenzimidazol-1-yl,3,5-dimethyl-1,2,4-triazol-4-yl,2-trifluoromethylimidazo[4,5-c]pyridin-1-yl,2-n-butylimidazo[4,5-c]pyridin-1-yl, 2-methylimidazo[4,5-b]pyridin-3-yl,2-methylimidazo[1,2-a]pyridin-3-yl, 2-ethylimidazo[4,5-c]pyridin-1-yl,7-methoxy-2-methylimidazo[4,5-d]pyrimidin-3-yl,2-methylimidazo[4,5-c]-pyridin-3-yl,2,4,6-trimethylimidazo[4,5-c]pyridin-1-yl, 2,4-dimethylimidazol-1-yl,2-methylimidazol-1-yl, 2,4,5-trimethylimidazol-1-yl,2,4-dimethyloxazol-5-yl, 2-methylimidazo[4,5-b]pyridin-1-yl,4-methylimidazol-1-yl, 2-methylpyridin-3-yl, 2,6-dimethylpyridin-3-yl,3,5-dimethyl-1,2,4-triazol-1-yl, 4-methyloxazol-5-yl,2,4-dimethylthiazol-5-yl, 6-methylimidazo[2,1-b]thiazol-5-yl, or4-methylthiazol-5-yl.

More preferably, R⁴ is 2-methylimidazo[4,5-c]pyridin-1-yl or2,4,6-trimethylimidazo[4,5-c]pyridin-1-yl.

Most preferably, R⁴ is 2-methylimidazo[4,5-c]pyridin-1-yl.

A preferred individual compound is4-(benzo[b]thien-3-yl)-1,4-dihydro-3-ethoxycarbonyl-6-methyl-2-[4-(2-methylimidazo[4,5-c]pyridin-1-yl)phenyl]-5-[N-(pyridin-2-yl)carbamoyl]pyridine.

The compounds of formula (I) contain at least one asymmetric centre andwill therefore exist as one or more pairs of enantiomers, and suchindividual enantiomers or individual pair of enantiomers may beseparable by physical methods, e.g. by fractional crystallisation orchromatography of the parent compounds or of a suitable salt orderivative thereof. The invention includes all the enantiomers of thecompounds of formula (I) whether separated or not.

The compounds of the invention of formula (I) may be prepared accordingto the Hantzsch synthesis as illustrated by the following reactionscheme: ##STR3## wherein R, R¹, R², R³ and R⁴ are as defined for formula(1).

In a typical procedure, the ketoester (IV) and the aldehyde (III) areheated together under reflux, preferably under a nitrogen atmosphere, ina suitable organic solvent, e.g. a C₁ -C₄ alkanol such as ethanol, forabout 15 minutes and then the 3-aminocrotonamide (II) is added.Alternatively, the mixture of the 3-aminocrotonamide (II), the ketoester(IV) and the aldehyde (III) can be heated together in the solvent.Optionally a small amount of a lower alkanoic acid, such as acetic acid,is added to neutralise the solution. The resulting solution can then beheated at from 50° to 130° C., preferably under reflux, until thereaction is essentially complete, typically in 24 hours or less. Theproduct of the formula (I) can then be isolated and purified byconventional procedures, for example by partition, recrystallisation orby chromatography.

Alternatively, in a modification of the above procedure, the ketoester(IV) and the aldehyde (III) are first reacted together, typically bystirring a slight excess of the ketoester with the aldehyde at roomtemperature in a suitable organic solvent, e.g. isopropyl alcohol,optionally containing piperidine as a catalyst, to give an intermediatecompound of formula (V): ##STR4## wherein R, R³ and R⁴ are as definedfor formula (I).

If desired, the intermediate compound (V) may be separated, for exampleby evaporating the reaction mixture to produce an oil, triturating theoil with water, and purifying the solid product obtained by filtrationand recrystallisation The compound of formula (V) may then be reactedwith the 3-aminocrotonamide (II), typically by heating the compoundstogether at from 50° to 130° C., preferably under reflux, in a suitableorganic solvent, e.g. a C₁ -C₄ alkanol, and preferably under a nitrogenatmosphere, to produce the compound of the formula (I) which again canbe isolated and purified by conventional methods.

The ketoesters (IV) are either known compounds or can be prepared by thefollowing methods:

(i) The ketoesters (IV) may be prepared by a Blaise reaction based on amodification of the literature method according to S.M. Hannick, Y.Kishi, J. Org. Chem., 48, 3833, (1983), as illustrated by the followingreaction sequence: ##STR5## wherein R³ and R⁴ are as defined for formula(I).

In a typical procedure, the benzonitrile derivative (VI) is added to asuspension of zinc dust and a few drops of the appropriate bromoacetatein a suitable dry organic solvent, such as tetrahydrofuran, under anitrogen atmosphere. The mixture is heated under reflux to initiate thereaction and further aliquots of the bromoacetate are then added. Oncompletion of the reaction and after cooling, aqueous potassiumcarbonate is added. After filtration, the filtrate is treated withdilute hydrochloric acid or with 20% aqueous trifluoroacetic acid,together with a suitable solvent such as dichloromethane. The reactionmixture is then neutralised and the ketoester (IV) isolated and purifiedby conventional procedures.

The benzonitrile derivatives (VI) are either known compounds or may beprepared by conventional methods in accordance with literatureprecedents.

(ii) An alternative method for preparing certain ketoesters (IV) isillustrated by the following reaction sequence: ##STR6## wherein "HaI"is halo preferabIy fluozo or bzomo, with the proviso that the hydrogenatom in R⁴ -H is attached to a ring nitrogen atom in R⁴. Optionally, acopper/cuprous bromide catalyst may be added in the first stage of thissequence but this is usually unnecessary where "Hal" is fluoro.

In a typical procedure, a mixture of the compound of the formula R⁴ -H,p-bromoacetophenone, copper bronze, cuprous bromide and anhydrouspotassium carbonate in a suitable solvent such as dryN-methylpyrrolidinone, is heated at about 150° C. under an atmosphere ofdry nitrogen The intermediate ketone (VII) obtained is isolated andpurified by conventional procedures, and is then added to a suspensionof sodium hydride in a suitable dry solvent, such as tetrahydrofuran,under a nitrogen atmosphere. The appropriate dialkyl carbonate is addedand the resultant mixture stirred at from 20° C. to reflux for asuitable period of time. Alternatively, the dialkyl carbonate may itselfbe used as the solvent. The ketoester (IV) obtained is isolated andpurified by conventional procedures.

The aldehydes of the formula (III) and the 3-aminocrotonamidederivatives (II) are either known compounds or can be prepared byconventional methods in accordance with literature precedents.

All of the above reactions are conventional and appropriate reagents andreaction conditions for their performance and procedures for isolatingthe desired products will be well known to those skilled in the art, inaccordance with literature precedents and by reference to the followingExamples and Preparations.

Pharmaceutically acceptable salts are readily prepared by mixingsolutions containing equimolar amounts of the free base and the desiredacid. The salt generally precipitates from solution and is collected byfiltration, or is recovered by evaporation of the solvent.

The activity of the compounds of the formula (I) is shown by theirability to inhibit the platelet aggregating activity of PAF in vitro.Testing is performed as follows:

Blood samples are taken from either rabbit or man into 0.1 vol disodiumethylenediaminetetraacetic acid buffer and the samples centrifuged for15 minutes to obtain platelet rich plasma. The plasma is furthercentrifuged to give a platelet pellet which is washed with a buffersolution (4 mM KH₂ PO₄, 6 mM Na₂ HPO₄, 100 mM NaCl, 0.1% glucose and0.1% bovine serum albumin, pH 7.25) and finally resuspended in buffersolution to a concentration of 2×10⁸ platelets/ml. A sample (0.5 ml) ispre-incubated for two minutes at 37° C. in a Paton aggregometer withstirring, either with vehicle alone, or with vehicle containing theparticular compound under test. PAF is added at a sufficientconcentration to give a maximum aggregating response in the absence oftest compound (10^("8) to 10⁻⁹ molar), and the platelet aggregation ismeasured by following the increase in light transmission of the solutionThe experiment is repeated in the presence of test compound at a rangeof concentrations and the concentration of compound required to reducethe response to 50% of its maximum value is recorded as the IC₅₀ value.

The activity of the compounds of formula (I) is also demonstrated invivo by their ability to protect mice from the lethal effect of aninjection of PAF. A mixture of PAF (50 ug/kg) and DL-propranolol (5mg/kg) in 0.9% w/v sodium chloride is injected (0.2 ml) via a tail veininto mice. The compounds under test are either injected into the tailvein immediately prior to the PAF/propranolol injection, or administeredorally by gavage two hours earlier. The compounds are tested at severaldoses in groups of 5 mice and the dose which reduces mortality to 50% isrecorded as the PD₅₀ value.

The compounds are also tested for their ability to reduce PAF-inducedbronchoconstriction in anaesthetised guinea pigs In this test, airwaysresistance and dynamic lung compliance are calculated from recordings ofairflow and transpleural pressure and calculation of tidal volume. Thebronchoconstriction induced by PAF (100 ng/kg) is determined. One hourafter the initial dose of PAF, the compound under test is administeredand the PAF challenge repeated. The ability of the compound to reducethe bronchoconstrictor effect of PAF is recorded as a ratio.

For therapeutic use the compounds of the formula (I) will generally beadministered in admixture with a pharmaceutical carrier selected withregard to the intended route of administration and standardpharmaceutical practice. For example, they may be administered orally inthe form of tablets containing such excipients as starch or lactose, orin capsules or ovules either alone or in admixture with excipients, orin the form of elixirs or suspensions containing flavouring or colouringagents. They may be injected parenterally, for example, intravenously,intramuscularly or subcutaneously. For parenteral administration, theyare best used in the form of a sterile aqueous solution which maycontain other substances, for example, enough salts or glucose to makethe solution isotonic with blood.

For administration to man in the curative or prophylactic treatment ofallergic bronchial conditions and arthritis, oral dosages of thecompounds will generally be in the range of from 2-1000 mg daily for anaverage adult patient (70 kg). Thus for a typical adult patient,individual tablets or capsules contain from 1 to 500 mg of activecompound, in a suitable pharmaceutically acceptable vehicle or carrier.Dosages for intravenous administration would typically be within therange from 1 to 10 mg per single dose as required for the treatment ofallergic and bronchial hyper-reactive conditions, inhalation via anebuliser or aerosol may be the preferred route of drug administration.Dose levels by this route would be within the range from 0.1 to 50 mgper single dose as required In practice the physician will determine theactual dosage which will be most suitable for an individual patient andit will vary with the age, weight and response of the particularpatient. The above dosages are exemplary of the average case but therecan, of course, be individual instances where higher or lower dosageranges are merited, and such are within the scope of this invention.

Thus, in a further aspect, the invention provides a pharmaceuticalcomposition comprising a compound of the formula (I), or apharmaceutically acceptable salt thereof, together with apharmaceutically acceptable diluent or carrier.

The invention also includes a compound of the formula (I), or apharmaceutically acceptable salt or composition thereof, for use as amedicament.

The invention further provides the use of a compound of the formula (I),or of a pharmaceutically acceptable salt or composition thereof, for themanufacture of a medicament for the treatment of allergic,hypersecretory and inflammatory conditions.

The invention yet further provides a method of treating an animal(including a human being) to cure or prevent allergic, hypersecretoryand inflammatory conditions, which comprises administering to saidanimal or human being, a therapeutically effective amount of a compoundof the formula (I), or a pharmaceutically acceptable salt or compositionthereof.

The preparation of the compounds of the invention is further illustratedby the following Examples:

EXAMPLE 14-(Benzo[b]thien-3-yl)-1,4-dihydro-3-ethoxycarbonyl-6-methyl-2-[4-(2-methylimidazo[4,5-c]pyridin-1-yl)nhenyl]-5-[N-(Pyridin-2-yl)carbamoyl]pnyridine##STR7##

A mixture of ethyl 4'-(2-methylimidazo[4,5-c]pyridin-1-yl)benzoylacetate(see Preparation 1) (646 mg, 2 mmol),3-amino-N-(pyridin-2-yl)crotonamide (353 mg, 2 mmol) andbenzo[b]thiophene-3-carboxaldehyde (324 mg, 2 mmol) in absolute ethanolwas heated under a nitrogen atmosphere under reflux for 6 hours. Thesolution was allowed to cool and the solvent was removed under reducedpressure. The residue was purified by flash chromatography (gradientelution with ethyl acetate changing to 7% diethylamine/ethyl acetate)and the fractions containing the product were combined and concentrated.The solid product obtained was triturated with ether/ethyl acetate andthen filtered to give the title compound as a colourless solid (250 mg,20%), m.p. 230°-238° C.

Analysis %:

Found: C, 68.14; H, 4.79; N, 13.17;

Calculated for C₃₆ H₃₀ N₆ O₃ S.1/2H₂ O: C, 67.96; H, 4.87; N, 13.21.

EXAMPLES 2 to 4

The following tabulated examples of general formula: ##STR8## wereprepared using similar conditions to those described for Example 1 usingthe appropriate heteroaromatic aldehyde, 3-aminocrotonamide andketoester derivatives.

    ______________________________________                                        Example                                                                       No.    R           m.p. (°C.)                                                                       Analysis (%)                                     ______________________________________                                                ##STR9##   240-250   Found: C,67.87; H,5.09; N,16.79; Calculated                                   for C.sub.33 H.sub.29 N.sub.7 O.sub.3.0.5                                     H.sub.2 O: C,68.26; H,5.21; N,16.89.             3                                                                                     ##STR10##  210-215   Found: C,66.63; H,5.01; N,16.66; Calculated                                   for C.sub.33 H.sub.29 N.sub.7 O.sub.3.1.25                                    H.sub.2 O: C,66.65; H,5.30; N,16.50.             4                                                                                     ##STR11##  235-245   Found: C,64.62; H,4.79; N,15.69; Calculated                                   for C.sub.33 H.sub.28 ClN.sub.7 O.sub.3.0.5                                   H.sub.2 O: C,64.44; H,4.75;                      ______________________________________                                                                     N,15.94.                                     

The following Preparation illustrates the preparation of the ketoesterused in the preceding Examples:

Preparation 1 ##STR12## (a) 4-[N-(4-Cyanophenyl)amino]-3-nitropyridine

According to the method of J.C.S. Perkin Trans. I, 1979, 135,p-cyanoaniIine (6 894 g, 58.4 mmol) was added to a solution of4-chloro-3-nitropyridine (9.26 g, 58.4 mmol) in ethanol (200 ml) and themixture was stirred at room temperature for 18 hours. The resultingyellow suspension was poured into 500 ml of ice-cold dilute ammonia andfiltered The solid was treated with 150 ml of boiling ethanol, cooled inice, and filtered to give the title compound as a bright yellow powder,(12.15 g), m.p. 210°-211° C.

¹ H-NMR (CDCl₃): δ=7.15 (1H, d, J=6 Hz), 7.45 (2H, d, J=9 Hz), 7.79 (2H,d, J=9 Hz), 8.43 (1H, d, J=6 Hz), 9.36 (1H, s), 9.80 (1H, br, s) p.p.m.

(b) 3-Amino-4-[N-(4-cyanophenyl)amino]pyridine

According to a modification of the method of Pharm. Helv. Acta, 50, 188(1975), tin(II) dichloride dihydrate (56.4 g, 250 mmol) was added to asuspension of 4-[N-(4-cyanophenyl)amino]-3-nitropyridine (see part (a))(12.0 g, 50 mmol) in 2N aqueous hydrochloric acid (35 ml), water (150ml) and ethanol (75 ml) and the resulting mixture was heated underreflux for 10 minutes under nitrogen. The mixture was cooled in ice,poured into ice-cold 2N aqueous sodium hydroxide (400 ml) and filteredThe creamy-coloured solid was washed with 2N aqueous sodium hydroxideand water, and then dried in a vacuum desiccator to provide the titlecompound, (9.31 g), which gradually turns reddish brown on exposure tolight and air.

¹ H-NMR (CDCl₃): δ=3.52 (2H, br s), 6.04 (1H, br s), 7.03 (2H, d, J=9Hz), 7.59 (2H, d, J=9 Hz), 8.07 (1H, m), 8.20 (1H, s) p.p.m.

(c) 1-(4-Cyanophenyl)-2-methylimidazo[4,5-c]pyridine

A mixture of 3-amino-4-[N-(4-cyanophenyl)amino]pyridine (see part (b))(9.31 g, 44.3 mmol), triethyl orthoacetate (40 ml) and acetic anhydride(30 ml) was heated under reflux for 2 hours under nitrogen, cooled, thenconcentrated under reduced pressure The brown residue was dissolved in1M hydrochloric acid and washed with ethyl acetate (200 ml). The aqueouslayer was rendered basic with saturated aqueous ammonia and extractedwith dichloromethane (3×200 ml). The combined extracts were washed withwater, dried (MgSO₄) and concentrated to give the title compound (6.5g), as a brown solid.

¹ H-NMR (CDCl₃): δ=2.61 (3H, s), 7.13 (1H, d, J=6 Hz), 7.58 (2H, d, J=9Hz), 7.98 (2H, d, J=9 Hz), 8.45 (1H, d, J=6 Hz), 9.11 (1H, s) p.p.m.

(d) Ethyl 4'-(2-methylimidazo[4,5-c]pyridin-1-yl)benzoylacetate

Zinc dust (894 mg, 13.7 mmol) was suspended in dry THF (3 ml) undernitrogen and sonicated at room temperature for 10 minutes. Ethylbromoacetate (2 drops) was added and the mixture was heated under refluxfor 5 minutes. A solution of1-(4-cyanophenyl)-2-methylimidazo[4,5-c]pyridine (640 mg, 2.74 mmol) indry THF (6 ml) was added and the mixture was refluxed for 5 minutes. Asolution of ethyl bromoacetate (1.822 g, 10.94 mmol) in dry THF (2 ml)was added dropwise over 1 hour at reflux and, after a further 10minutes, the mixture was allowed to cool to room temperature. 50%aqueous potassium carbonate (1 ml) was added and the mixture was stirredfor 45 minutes at room temperature then filtered through "Arbocel"(Trade Mark), a cellulose based filter aid, washing with THF. Thefiltrate was concentrated under reduced pressure to give a yellow gum.This material was treated with a mixture of 20% aqueous trifluoroaceticacid (10 ml) and dichloromethane (50 ml) and stirred at room temperaturefor 15 minutes. The mixture was neutralised by the addition of saturatedaqueous sodium bicarbonate and then extracted with dichloromethane (2×30ml). The combined extracts were dried (MgSO₄), concentrated underreduced pressure and the crude product was purified by flashchromatography on silica gel (eluting with 10% changing to 20%methanol/ethyl acetate) to give, after combination and evaporation ofappropriate fractions, the title compound (480 mg, 54%), as a yellowgum. This material was rechromatographed (eluting with 7:1 ethylacetate/methanol) to give, after combination and evaporation ofappropriate fractions, a white solid, m.p. 111°-112° C. (ethyl acetate).

¹ H-NMR (CDCl₃): δ=1.32 ((3H, t, J=6 Hz), 2.61 (3H, s), 4.09 (2H, s),4.28 (2H, q, J=6 Hz), 7.16 (1H, d, J=6 Hz), 7.55 (2H, d, J=9 Hz), 8.23(2H, d, J=9 Hz), 8.46 (1H, d, J=6 Hz), 9.09 (1H, s) p.p.m.

We claim:
 1. A compound of the formula ##STR13## or a pharmaceuticallyacceptable salt thereof, wherein: R is a thienyl, benzothienyl, furyl orbenzofuranyl group, said group being optionally substituted by up tothree substituents each independently selected from the group consistingof nitro, halo, (C₁ -C₄)alkyl, (C₁ -C₄)alkoxy, hydroxy, aryl(C₁-C₄)alkoxy, fluoro (C₁ -C₄)alkoxy, (C₁ -C₄)alkylthio, (C₁-C₄)alkanesulphonyl, trifluoromethyl and cyano;R¹ is hydrogen or (C₁-C₄)alkyl; R² is pyridyl, pyrimidinyl, pyridazinyl or pyrazinyl; R³ is(C₁ -C₄)alkyl or aryl(C₁ -C₄)alkyl; and R⁴ is an imidazolyl or triazolylgroup, said group being optionally benzo-, pyrido-, pyridazino-,pyrimido- or pyrazino-fused and optionally substituted by up to threesubstituents each independently selected from the group consisting of(C₁ -C₄)alkyl, (C₁ -C₄)alkoxy, trifluoromethyl and halo.
 2. A compoundaccording to claim 1 wherein R² is pyridyl.
 3. A compound according toclaim 2 wherein R is benzothien-3-yl.
 4. A compound according to claim 3wherein R¹ is hydrogen.
 5. A compound according to claim 4 wherein R² ispyridin-2-yl.
 6. A compound according to claim 5 wherein R³ is methyl,ethyl or benzyl.
 7. A compound according to claim 6 wherein R³ is ethyl.8. A compound according to claim 7 wherein R⁴ is2-methylimidazo[4,5-c]pyridin-1-yl or2,4,6-trimethylimidazo[4,5-c]pyridin-1-yl.
 9. The compound according toclaim 8 wherein R⁴ is 2-methylimidazo[4,5-c]pyridin-1-yl.
 10. Apharmaceutical composition comprising a hypoallergenic amount of acompound according to claim 1 and a pharmaceutically acceptable carrieror diluent.
 11. A method of treating allergies in a mammal in need ofsuch treatment comprising administering to said mammal a hypoallergenicamount of a compound according to claim 1.